CFLAR is a critical regulator of cerebral ischaemia-reperfusion injury through regulating inflammation and endoplasmic reticulum (ER) stress
Stroke is a leading cause of mortality and disability globally. Cerebral ischaemia-reperfusion (I/R) injury is characterized by significant inflammation and extensive cell death. Multiple signaling pathways play essential roles in the process, and identifying the unclear crucial regulators of these...
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doaj-ad124f7aefa5405cbf7ae530b3244e182021-05-20T07:38:41ZengElsevierBiomedicine & Pharmacotherapy0753-33222019-09-01117CFLAR is a critical regulator of cerebral ischaemia-reperfusion injury through regulating inflammation and endoplasmic reticulum (ER) stressWang Xiaohong0Zhao Jun1Guo Hongmei2Qinqin Fan3Department of Neurology, Shandong Provincial ENT Hospital, Shandong Provincial ENT Hospital affiliated to Shandong University, 250022, ChinaDepartment of Internal Medicine, 316thHospital of PLA, Beijing 100091, ChinaDepartment of Neurology, Shandong Provincial ENT Hospital, Shandong Provincial ENT Hospital affiliated to Shandong University, 250022, ChinaDepartment of Internal Medicine, Ankang City Center Hospital, Ankang, Shaanxi 725000, China; Corresponding author at: Department of Internal Medicine, Ankang City Center Hospital, No. 85, Jinzhou South Road, Hanbin District, Ankang, Shaanxi, 725000, China.Stroke is a leading cause of mortality and disability globally. Cerebral ischaemia-reperfusion (I/R) injury is characterized by significant inflammation and extensive cell death. Multiple signaling pathways play essential roles in the process, and identifying the unclear crucial regulators of these pathways may provide promising targets for treatment. CASP8 and FADD-like apoptosis regulator (CFLAR) is expressed in multiple organs to regulate inflammation. Here, we reported that CFLAR expression was markedly reduced in brain samples of mice with middle cerebral artery occlusion (MCAO) stroke. Furthermore, CFLAR knockdown markedly elevated the neurological deficit, brain water content and the infarct volume. In addition, significantly promoted inflammation and endoplasmic reticulum (ER) stress was detected in brain tissues of mice after MCAO, as evidenced by the promoted expression of p-IκBα, p-nuclear factor (NF)-κB (p65), glucose-regulated protein 78 (GRP78), PKR-like ER kinase (PERK), activating transcription factor-6 (ATF-6) and cleaved Caspase-12. Notably, MCAO-induced cerebral I/R injury was markedly alleviated in mice over-expressing CFLAR through suppressing inflammation and ER stress. Furthermore, our in vitro results indicated that oxygen-glucose deprivation (OGD)-induced cell death was evidently ameliorated by CFLAR over-expression. In contrast, the cell death triggered by OGD was accelerated by CFLAR knockdown in vitro through enhancing Caspase-3 cleavage, and this effect was obviously ameliorated by the blockage of ER stress using 4-phenyl butyric acid (4-PBA). Collectively, these results demonstrated that CFLAR could be considered as a novel candidate to develop effective therapeutic treatment against cerebral I/R injury.http://www.sciencedirect.com/science/article/pii/S0753332219323157Cerebral I/R injuryCFLARInflammationER stressCell death |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Wang Xiaohong Zhao Jun Guo Hongmei Qinqin Fan |
spellingShingle |
Wang Xiaohong Zhao Jun Guo Hongmei Qinqin Fan CFLAR is a critical regulator of cerebral ischaemia-reperfusion injury through regulating inflammation and endoplasmic reticulum (ER) stress Biomedicine & Pharmacotherapy Cerebral I/R injury CFLAR Inflammation ER stress Cell death |
author_facet |
Wang Xiaohong Zhao Jun Guo Hongmei Qinqin Fan |
author_sort |
Wang Xiaohong |
title |
CFLAR is a critical regulator of cerebral ischaemia-reperfusion injury through regulating inflammation and endoplasmic reticulum (ER) stress |
title_short |
CFLAR is a critical regulator of cerebral ischaemia-reperfusion injury through regulating inflammation and endoplasmic reticulum (ER) stress |
title_full |
CFLAR is a critical regulator of cerebral ischaemia-reperfusion injury through regulating inflammation and endoplasmic reticulum (ER) stress |
title_fullStr |
CFLAR is a critical regulator of cerebral ischaemia-reperfusion injury through regulating inflammation and endoplasmic reticulum (ER) stress |
title_full_unstemmed |
CFLAR is a critical regulator of cerebral ischaemia-reperfusion injury through regulating inflammation and endoplasmic reticulum (ER) stress |
title_sort |
cflar is a critical regulator of cerebral ischaemia-reperfusion injury through regulating inflammation and endoplasmic reticulum (er) stress |
publisher |
Elsevier |
series |
Biomedicine & Pharmacotherapy |
issn |
0753-3322 |
publishDate |
2019-09-01 |
description |
Stroke is a leading cause of mortality and disability globally. Cerebral ischaemia-reperfusion (I/R) injury is characterized by significant inflammation and extensive cell death. Multiple signaling pathways play essential roles in the process, and identifying the unclear crucial regulators of these pathways may provide promising targets for treatment. CASP8 and FADD-like apoptosis regulator (CFLAR) is expressed in multiple organs to regulate inflammation. Here, we reported that CFLAR expression was markedly reduced in brain samples of mice with middle cerebral artery occlusion (MCAO) stroke. Furthermore, CFLAR knockdown markedly elevated the neurological deficit, brain water content and the infarct volume. In addition, significantly promoted inflammation and endoplasmic reticulum (ER) stress was detected in brain tissues of mice after MCAO, as evidenced by the promoted expression of p-IκBα, p-nuclear factor (NF)-κB (p65), glucose-regulated protein 78 (GRP78), PKR-like ER kinase (PERK), activating transcription factor-6 (ATF-6) and cleaved Caspase-12. Notably, MCAO-induced cerebral I/R injury was markedly alleviated in mice over-expressing CFLAR through suppressing inflammation and ER stress. Furthermore, our in vitro results indicated that oxygen-glucose deprivation (OGD)-induced cell death was evidently ameliorated by CFLAR over-expression. In contrast, the cell death triggered by OGD was accelerated by CFLAR knockdown in vitro through enhancing Caspase-3 cleavage, and this effect was obviously ameliorated by the blockage of ER stress using 4-phenyl butyric acid (4-PBA). Collectively, these results demonstrated that CFLAR could be considered as a novel candidate to develop effective therapeutic treatment against cerebral I/R injury. |
topic |
Cerebral I/R injury CFLAR Inflammation ER stress Cell death |
url |
http://www.sciencedirect.com/science/article/pii/S0753332219323157 |
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